Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. To date, there is still no effective antihypercholesterolemic agent commercially available that has found wide patient acceptance. The bile acid sequestrants seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
There are agents known, however, that are very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. These agents include the natural fermentation products compactin and mevinolin and a variety of semisynthetic and totally synthetic analogs thereof.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR2## wherein X is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino or acetylamino;
R' is ##STR3## wherein Q is ##STR4## R.sub.2 is hydrogen or hydroxy; R.sub.1 is hydrogen or methyl; and PA0 a, b, c and d are single bonds, one of a, b, c and d is a double bond or a and c or b and d are double bonds provided that when a is a double bond, Q is ##STR5## PA0 R.sub.3 and R.sub.4 are independently C.sub.1-3 alkyl, fluoro, bromo or chloro; and PA0 R.sub.5 is phenyl, benzyloxy, substituted phenyl or substituted benzyloxy in which the phenyl group in each case is substituted with one or more substituents selected from C.sub.1-3 alkyl, fluoro, bromo or chloro. PA0 R.sup.1 is hydrogen or methyl; PA0 A is ##STR10## in which R.sup.2 is hydrogen or hydroxyl; B is ##STR11## in which R.sup.3 is hydrogen or hydroxyl; a, b, c and d represent single bonds, one of a, b, c and d represents a double bond or both a and c or both b and d represent double bonds, provided that when a is a double bond, A is ##STR12## and when d is a double bond, B is ##STR13## or PA0 R.sup.4 and R.sup.5 are independently C.sub.1-3 alkyl, fluoro, bromo or chloro; and PA0 R.sup.6 is phenyl, benzyloxy, substituted phenyl or substituted benzyloxy in which the phenyl group in each case is substituted with one or more substituents selected from C.sub.1-3 alkyl, fluoro, bromo or chloro; PA0 R.sup.7 is hydrogen or C.sub.1-6 alkyl; PA0 R.sup.8 is C.sub.1-6 alkyl; and PA0 R.sup.9 is C.sub.1-6 alkyl, C.sub.1-6 acyloxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyloxy C.sub.1-6 alkyl or a group selected from
The totally synthetic antihypercholesterolemic compounds are disclosed in U.S. Pat. No. 4,375,475 and have the following general structural formulae: ##STR6## wherein R" is: ##STR7## wherein: E is --CH.sub.2 --, --CH.sub.2 CH.sub.2 -- or --CH.dbd.CH--;